Diverse polyubiquitin chains accumulate following 26S proteasomal dysfunction in mammalian neurones
Research highlights
▶ An extensive repertoire of non-Lys63-linked polyubiquitin chains function in 26S proteasomal targeting in mammalian neurones. ▶ Mass spectrometry approaches can be used to investigate ubiquitin–ubiquitin isopeptide linkages in their physiological context in vivo.
Section snippets
Acknowledgements
This work was supported by a Parkinson's UK Senior Research Fellowship (F-0702) and a Research Scholar Grant from the American Cancer Society (RSG-09-181).
References (34)
- et al.
UBXD7 binds multiple ubiquitin ligases and implicates p97 in HIF1alpha turnover
Cell
(2008) - et al.
Ubiquitin chains are remodeled at the proteasome by opposing ubiquitin ligase and deubiquitinating activities
Cell
(2006) - et al.
Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain
Cell
(2000) - et al.
The lysine 48 and lysine 63 ubiquitin conjugates are processed differently by the 26s proteasome
The Journal of Biological Chemistry
(2009) - et al.
Mechanism of ubiquitin-chain formation by the human anaphase-promoting complex
Cell
(2008) - et al.
A proteolytic pathway that recognizes ubiquitin as a degradation signal
The Journal of Biological Chemistry
(1995) - et al.
Certain pairs of ubiquitin-conjugating enzymes (E2s) and ubiquitin–protein ligases (E3s) synthesize nondegradable forked ubiquitin chains containing all possible isopeptide linkages
The Journal of Biological Chemistry
(2007) - et al.
Identification of residues on Hsp70 and Hsp90 ubiquitinated by the cochaperone CHIP
Journal of Molecular Biology
(2010) - et al.
Immunoreactivity to Lys63-linked polyubiquitin is a feature of neurodegeneration
Neuroscience Letters
(2009) - et al.
Polyubiquitin chains: polymeric protein signals
Current Opinion in Chemical Biology
(2004)
A series of ubiquitin binding factors connects CDC48/p97 to substrate multiubiquitylation and proteasomal targeting
Cell
Definitive evidence for Ufd2-catalyzed elongation of the ubiquitin chain through Lys48 linkage
Biochemical and Biophysical Research Communications
Regulating post-translational modifications of the eukaryotic replication clamp PCNA
DNA Repair
Quantitative proteomics reveals the function of unconventional ubiquitin chains in proteasomal degradation
Cell
Reconstitution of the RIG-I pathway reveals a signaling role of unanchored polyubiquitin chains in innate immunity
Cell
Depletion of 26S proteasomes in mouse brain neurons causes neurodegeneration and Lewy-like inclusions resembling human pale bodies
The Journal of Neuroscience
Global changes to the ubiquitin system in Huntington's disease
Nature
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